4ea3

From Proteopedia

(Difference between revisions)

Current revision

Structure of the N/OFQ Opioid Receptor in Complex with a Peptide Mimetic

Structural highlights

4ea3 is a 2 chain structure with sequence from Escherichia coli and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.013Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

C562_ECOLX Electron-transport protein of unknown function.OPRX_HUMAN G-protein coupled opioid receptor that functions as a receptor for the endogenous neuropeptide nociceptin. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling via G proteins mediates inhibition of adenylate cyclase activity and calcium channel activity. Arrestins modulate signaling via G proteins and mediate the activation of alternative signaling pathways that lead to the activation of MAP kinases. Plays a role in modulating nociception and the perception of pain. Plays a role in the regulation of locomotor activity by the neuropeptide nociceptin.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Members of the opioid receptor family of G-protein-coupled receptors (GPCRs) are found throughout the peripheral and central nervous system, where they have key roles in nociception and analgesia. Unlike the 'classical' opioid receptors, delta, kappa and mu (delta-OR, kappa-OR and mu-OR), which were delineated by pharmacological criteria in the 1970s and 1980s, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP, also known as ORL-1) was discovered relatively recently by molecular cloning and characterization of an orphan GPCR. Although it shares high sequence similarity with classical opioid GPCR subtypes ( approximately 60%), NOP has a markedly distinct pharmacology, featuring activation by the endogenous peptide N/OFQ, and unique selectivity for exogenous ligands. Here we report the crystal structure of human NOP, solved in complex with the peptide mimetic antagonist compound-24 (C-24) (ref. 4), revealing atomic details of ligand-receptor recognition and selectivity. Compound-24 mimics the first four amino-terminal residues of the NOP-selective peptide antagonist UFP-101, a close derivative of N/OFQ, and provides important clues to the binding of these peptides. The X-ray structure also shows substantial conformational differences in the pocket regions between NOP and the classical opioid receptors kappa (ref. 5) and mu (ref. 6), and these are probably due to a small number of residues that vary between these receptors. The NOP-compound-24 structure explains the divergent selectivity profile of NOP and provides a new structural template for the design of NOP ligands.

Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic.,Thompson AA, Liu W, Chun E, Katritch V, Wu H, Vardy E, Huang XP, Trapella C, Guerrini R, Calo G, Roth BL, Cherezov V, Stevens RC Nature. 2012 May 16;485(7398):395-9. doi: 10.1038/nature11085. PMID:22596163^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Serhan CN, Fierro IM, Chiang N, Pouliot M. Cutting edge: nociceptin stimulates neutrophil chemotaxis and recruitment: inhibition by aspirin-triggered-15-epi-lipoxin A4. J Immunol. 2001 Mar 15;166(6):3650-4. doi: 10.4049/jimmunol.166.6.3650. PMID:11238602 doi:http://dx.doi.org/10.4049/jimmunol.166.6.3650
↑ Spampinato S, Di Toro R, Alessandri M, Murari G. Agonist-induced internalization and desensitization of the human nociceptin receptor expressed in CHO cells. Cell Mol Life Sci. 2002 Dec;59(12):2172-83. doi: 10.1007/s000180200016. PMID:12568343 doi:http://dx.doi.org/10.1007/s000180200016
↑ Thompson AA, Liu W, Chun E, Katritch V, Wu H, Vardy E, Huang XP, Trapella C, Guerrini R, Calo G, Roth BL, Cherezov V, Stevens RC. Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature. 2012 May 16;485(7398):395-9. doi: 10.1038/nature11085. PMID:22596163 doi:10.1038/nature11085
↑ Zhang NR, Planer W, Siuda ER, Zhao HC, Stickler L, Chang SD, Baird MA, Cao YQ, Bruchas MR. Serine 363 is required for nociceptin/orphanin FQ opioid receptor (NOPR) desensitization, internalization, and arrestin signaling. J Biol Chem. 2012 Dec 7;287(50):42019-30. doi: 10.1074/jbc.M112.405696. Epub 2012, Oct 19. PMID:23086955 doi:http://dx.doi.org/10.1074/jbc.M112.405696
↑ Mollereau C, Parmentier M, Mailleux P, Butour JL, Moisand C, Chalon P, Caput D, Vassart G, Meunier JC. ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization. FEBS Lett. 1994 Mar 14;341(1):33-8. doi: 10.1016/0014-5793(94)80235-1. PMID:8137918 doi:http://dx.doi.org/10.1016/0014-5793(94)80235-1
↑ Thompson AA, Liu W, Chun E, Katritch V, Wu H, Vardy E, Huang XP, Trapella C, Guerrini R, Calo G, Roth BL, Cherezov V, Stevens RC. Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature. 2012 May 16;485(7398):395-9. doi: 10.1038/nature11085. PMID:22596163 doi:10.1038/nature11085

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4ea3"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4ea3]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EA3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EA3 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0NN:1-BENZYL-N-[3-(1H,3H-SPIRO[2-BENZOFURAN-1,4-PIPERIDIN]-1-YL)PROPYL]-D-PROLINAMIDE'>0NN</scene>, <scene name='pdbligand=OLA:OLEIC+ACID'>OLA</scene>, <scene name='pdbligand=OLB:(2S)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLB</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.013&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0NN:1-BENZYL-N-[3-(1H,3H-SPIRO[2-BENZOFURAN-1,4-PIPERIDIN]-1-YL)PROPYL]-D-PROLINAMIDE'>0NN</scene>, <scene name='pdbligand=OLA:OLEIC+ACID'>OLA</scene>, <scene name='pdbligand=OLB:(2S)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLB</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ea3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ea3 OCA], [https://pdbe.org/4ea3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ea3 RCSB], [https://www.ebi.ac.uk/pdbsum/4ea3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ea3 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/C562_ECOLX C562_ECOLX]] Electron-transport protein of unknown function.[[https://www.uniprot.org/uniprot/OPRX_HUMAN OPRX_HUMAN]] G-protein coupled opioid receptor that functions as receptor for the endogenous neuropeptide nociceptin. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling via G proteins mediates inhibition of adenylate cyclase activity and calcium channel activity. Arrestins modulate signaling via G proteins and mediate the activation of alternative signaling pathways that lead to the activation of MAP kinases. Plays a role in modulating nociception and the perception of pain. Plays a role in the regulation of locomotor activity by the neuropeptide nociceptin.<ref>PMID:11238602</ref> <ref>PMID:12568343</ref> <ref>PMID:22596163</ref> <ref>PMID:23086955</ref> <ref>PMID:8137918</ref>
+[https://www.uniprot.org/uniprot/C562_ECOLX C562_ECOLX] Electron-transport protein of unknown function.[https://www.uniprot.org/uniprot/OPRX_HUMAN OPRX_HUMAN] G-protein coupled opioid receptor that functions as a receptor for the endogenous neuropeptide nociceptin. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling via G proteins mediates inhibition of adenylate cyclase activity and calcium channel activity. Arrestins modulate signaling via G proteins and mediate the activation of alternative signaling pathways that lead to the activation of MAP kinases. Plays a role in modulating nociception and the perception of pain. Plays a role in the regulation of locomotor activity by the neuropeptide nociceptin.<ref>PMID:11238602</ref> <ref>PMID:12568343</ref> <ref>PMID:22596163</ref> <ref>PMID:23086955</ref> <ref>PMID:8137918</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==

4ea3

From Proteopedia

Current revision

Structure of the N/OFQ Opioid Receptor in Complex with a Peptide Mimetic

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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